5,6,7,8-Tetrahydronaphthalene hypotensive agents

ABSTRACT

5,6,7,8-Tetrahydronaphthalenes having the structure ##STR1## and the pharmaceutically acceptable salts thereof, are useful as blood pressure lowering agents. In the above formula R 1  can be hydrogen or alkyl; R 2  is alkyl; R 3  and R 4  can each be hydrogen, hydroxyl, alkoxy, or arylalkoxy, but both cannot be hydroxyl. Those compounds wherein at least one of R 3  and R 4  is other than hydrogen are novel, and constitute a part of this invention.

This application is a continuation-in-part of U.S. Patent application,Serial No. 268,314, filed July 3, 1972, now abandoned.

BRIEF DESCRIPTION OF THE INVENTION

5,6,7,8-Tetrahydronaphthalenes having the structure ##STR2## and thepharmaceutically acceptable salts thereof, have been found to behypotensive agents. Compounds of formula I wherein at least one of R₃and R₄ are other than hydrogen are novel, and as such constitute a partof this invention.

In formula I, and throughout the specification, the symbols are asdefined below:

R₁ can be hydrogen or alkyl;

R₂ is alkyl; and

R₃ and R₄ can each be hydrogen, hydroxyl, alkoxy, or arylalkoxy, but atleast one of R₃ and R₄ must be other than hydroxyl.

The term "alkyl" as used throughout the specification refers to bothstraight and branched chain alkyl groups having from one to eight carbonatoms, e.g., methyl, ethyl, propyl, isopropyl, t-butyl, heptyl, octyl,2,2,4-trimethylpentyl, etc. Alkyl groups having one to four carbon atomsare preferred.

The term "alkoxy" as used throughout the specification refers to a groupof the formula alkyl-O-, wherein alkyl is as defined above.

The term "arylalkoxy" as used throughout the specification refers to analkoxy group (defined above) having the alkyl portion of the moleculesubstituted with an aryl group.

The term "aryl" as used throughout the specification refers to phenyl orphenyl substituted with one or two of the following substituents:halogen, alkyl, or alkoxy.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula I can be prepared from naphthalene derivativeshaving the structure ##STR3## In formula II, and throughout thespecification R'₃ and R'₄ can each be hydrogen or hydroxyl. Anaphthalene of formula II can be reduced with a metal such as sodium orlithium in liquid ammonia containing an alkanol such as ethanol,isopropanol, t-butanol, etc. to obtain a 5,8-dihydronaphthalene havingthe structure ##STR4## To prepare the 5,8-dihydronaphthalene startingmaterials necessary for the preparation of the compounds of formula Iwherein R₃ or R₄ is alkoxy or arylalkoxy, the corresponding hydroxylderivative of formula III is reacted with an alkyl halide or arylalkylhalide to yield a 5,8-dihydronaphthalene having the structure ##STR5##In formula IV, and throughout the specification, R"₃ and R"₄ can each bealkoxy or arylalkoxy. The reaction is carried out in a polar organicsolvent, e.g., dimethylsulfoxide, dimethylformamide, etc., in thepresence of an alkali metal alkoxide, e.g., sodium methoxide, potassiumethoxide, etc.

Reaction of a 5,8-dihydronaphthalene of formula III or formula IV withm-chloroperbenzoic acid yields a 5,6,7,8-tetrahydro-6,7-epoxynaphthalenehaving the structure ##STR6## The reaction can be carried out by mixingm-chloroperbenzoic acid with a solution of a 5,8-dihydronaphthalene inan organic solvent, e.g., ethyl acetate. The resulting mixture is addedto a mixture of ethyl ether and aqueous sodium bicarbonate, and mixed toform a 5,6,7,8-tetrahydro-6,7-epoxynaphthalene of formula V.

The compounds of formula I can be prepared by reacting a5,6,7,8-tetrahydro-6,7-epoxynaphthalene of formula V with an aminehaving the formula ##STR7## The reaction can be run in an organicsolvent, e.g., ethanol, xylene, etc., at a temperature of from 50° C to140° C, preferably from 110° C to 140° C. The reaction is run for about5 hours to 24 hours, preferably 16 hours to 24 hours.

Other methods for the preparation of the compounds of formula I will bereadily apparent to a person of ordinary skill in organic chemistry. Thepreparation of compounds of formula I containing an alkoxy group in thearomatic ring can be accomplished by first preparing the correspondingphenolic derivative. Reaction of the phenolic compound with adiazoalkane in an organic solvent yields the desired alkoxy derivative.

Both the cis and trans isomers of the compounds of formula I arespecifically contemplated for use in this invention. The cis compoundscan be prepared from the corresponding trans compounds using aninversion technique. In this procedure a trans vicinal primary aminoalcohol is reacted with benzoyl chloride in benzene in the presence of abase to yield the corresponding benzamidoalcohol. The benzamidoalcoholis then converted to the corresponding cyclic oxazolidine with thionylchloride, which is hydrolyzed in dilute acid to the cis vicinal primaryamino alcohol and alkylated by well known methods, e.g., condensationwith a ketone followed by catalytic reduction.

The compounds of formula I form acid addition salts with inorganic andorganic acids. These acid addition salts frequently provide useful meansfor isolating the products from reaction mixtures by forming the salt ina medium in which it is insoluble. The free base may then be obtained byneutralization, e.g., with a base such as sodium hydroxide. Then anyother salt may again be formed from the free base and the appropriateinorganic or organic acid. Illustrative are the hydrohalides, especiallythe hydrochloride and hydrobromide which are preferred, sulfate,nitrate, phosphate, borate, acetate, tartrate, maleate, citrate,succinate, benzoate, ascorbate, salicylate, methanesulfonate,benzenesulfonate, toluenesulfonate and the like.

The 5,6,7,8-tetrahydronaphthalenes of formula I, and thepharmaceutically acceptable acid addition salts thereof, are useful ashypotensive agents in mammals, e.g., domestic animals such as dogs,cats, etc. Daily doses of from 5 to 50 mg/kg, preferably about 5 to 25mg/kg can be administered in single or divided doses.

The active compounds of the present invention are administered orally,for example, with an inert diluent or with an assimilable ediblecarrier, or they may be enclosed in hard or soft gelatin capsules, orthey may be compressed into tablets, or they may be incorporateddirectly with the food of the diet. For oral therapeutic administration,the active compounds of this invention may be incorporated withexcipients and used in the form of tablets, troches, capsules, elixirs,suspensions, syrups, wafers, chewing gum, and the like. Suchcompositions and preparations should contain at least 0.1% of activecompound. The percentage in the compositions and preparations may, ofcourse, be varied and may conveniently be between about 5% to about 75%or more of the weight of the unit. The amount of active compound in suchtherapeutically useful compositions or preparations is such that asuitable dosage will be obtained. Preferred compositions or preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between about 5 and 250 milligrams of activecompound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder such as gum tragacanth, acacia, corn starch orgelatin; an excipient such as dicalcium phosphate; a disintegratingagent such as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain in addition to materials of theabove type a liquid carrier such as a fatty oil. Various other materialsmay be present as coatings or to otherwise modify the physical form ofthe dosage unit, for instance, tablets, pills, or capsules may be coatedwith shellac, sugar, or both. A syrup or elixir may contain the activecompounds, sucrose as a sweetening agent, methyl and propyl parabens aspreservatives, a dye and a flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amountsemployed.

The following examples further illustrate the preparation of thecompounds of this invention.

EXAMPLE 1 6,7-trans-5,6,7,8-Tetrahydro-7(and 6)-(isopropylamino)-1,6(and7)-naphthalenediol, hydrochloride A.6,7-Epoxy-5,6,7,8-tetrahydro-1-naphthol acetate

A solution of 101 g of 5,8-dihydro-1-naphthol acetate in 1.5 liters ofmethylene chloride is cooled to 0° C and 89 g of m-chloroperbenzoic acidis added over a period of 5 minutes and the mixture is stirred overnightat room temperature.

The suspension is poured into a mixture of 500 ml of 10% sodiumhydroxide and 1000 g of ice. The aqueous layer is extracted withmethylene chloride (two 500 ml portions), and the combined organiclayers are washed with water and saturated sodium chloride solution,dried and evaporated in vacuo to give 105 g of pink solid.

B. 6,7-trans-5,6,7,8-Tetrahydro-7(and 6)-(isopropylamino)-1,6(and7)-naphthalenediol, hydrochloride

A mixture of 6,7-epoxy-5,6,7,8-tetrahydro-1-naphthol acetate (10.2 g)and isopropylamine is charged to a small bomb and heated overnight in anoil bath maintained at 100° C. After cooling, the excess amine isremoved in vacuo leaving a dark brown viscous material which ischromatographed, on activity 3 neutral alumina. Fractions eluted with10-20% methanol in chloroform yield crystalline material on standingunder hexane. Two recrystallizations from ether give a sample melting at112°-117° C. This is dissolved in isopropyl alcohol-ether and convertedto the hydrochloride by adding a solution of hydrochloric acid inisopropyl alcohol. The white hydrochloride is recrystallized fromisopropyl alcohol-methanol-ether to give 2.2 g of the title product,melting point 207°-210° C.

EXAMPLE 2 trans-7(and 6)-(Dimethylamino)-5,6,7,8-tetrahydro-1,6(and7)-naphthalenediol

A mixture of 10.2 g of 6,7-epoxy-5,6,7,8-tetrahydro-1-naphthol acetate(prepared as described in Example 1) and 50 ml of anhydrousdimethylamine is heated overnight in a small Paar bomb (oil bathtemperature = 100° C ± 5° C, internal pressure = 140 psi). After coolingthe reaction mixture, excess dimethylamine and N,N-dimethylacetamide areremoved in vacuo, yielding 11.65 g of dark viscous oil. This material isdissolved in benzene and applied to a column of basic alumina (ActivityIII, 350 g). Elution with benzene and benzene/chloroform mixtures givesmall amounts of non-polar material. Elution with chloroform yields 4.36g of crudetrans-7-(dimethylamino)-5,6,7,8-tetrahydro-1,6-naphthalenediol, meltingpoint 179°-183° C after trituration with ether. Elution with 5%methanol/chloroform gives 3.12 g oftrans-6-(dimethylamino)-5,6,7,8-tetrahydro-1,7-naphthalenediol, meltingpoint 168°-170° C after trituration with ether.

Two recrystallizations from ethyl acetate/benzene oftrans-7-(dimethylamino)-5,6,7,8-tetrahydro-1,6-naphthalenediol give 1.93g of colorless crystals melting point 181.5°-183.5° C.

Two recrystallizations from ethyl acetate/benzene oftrans-7-(dimethylamino)-5,6,7,8-tetrahydro-1,6-naphthalenediol give 1.22g of colorless crystals, melting point 169.5°-171° C.

Anal. Calc'd for C₁₂ H₁₇ NO₂ : C, 69.54; H, 8.27; N, 6.75.

Found: C, 69.69; H, 8.47; N, 6.76.

EXAMPLE 3trans-1,2,3,4-Tetrahydro-3-[(1-methylethyl)amino]-5,8-dimethoxy-2-naphthalenolA. 4a,5,8,8a-Tetrahydro-1,4-naphthaquinone

The 1,3-butadiene adduct of p-quinone is prepared as described by vanTamelen, et al, JACS, 91, 7315 (1969). An amount of 500 ml of liquified1,3-butadiene is added to a mixture of 500 g of p-quinone in 3.5 litersof benzene at 0° C. The 5-liter round bottom flask is sealed with atightly wired rubber stopper and stored in the dark at room temperaturefor 23 days. The mixture is treated with charcoal, filtered, andevaporated in vacuo. Recrystallization from petroleum ether (12 liters)gives 456.5 g of 4a,5,8,8a-tetrahydro-1,4-naphthaquinone, melting point52°-57° C.

B. 5,8-Dihydro-1,4naphthalenediol

As described in Ber., 62, 2345 (1929) an amount of 1 ml of a saturatedsolution of hydrogen bromide gas in glacial acetic acid is added to amixture of 104 g of 4a,5,8,8a-tetrahydro-1,4-naphthaquinone in 174 ml ofglacial acetic acid. The solution is stirred for 5 minutes at roomtemperature before a vigorous exothermic reaction takes place(temperature 25°-110° C over a 2 minute period) giving a light tansolid. The solid is collected and washed with hexane to give 100.5 g of5,8-dihydro-1,4naphthalenediol, melting point 208°-211° C.

C. 5,8-Dihydro-1,4-dimethoxynaphthalene

A suspension of 63.18 g (0.39 mole) of 5,8-dihydro-1,4-naphthalenediolin 300 ml of absolute ethanol is heated briefly until solution isachieved. To this hot stirred solution is added alternately in fiveportions a solution of 40 g of sodium hydroxide in 100 ml of water, and120 g of dimethyl sulfate. The heat evolved during the addition causesthe solution to reflux. After the addition is complete a solution of 10g of sodium hydroxide in 20 ml of water is added and the mixture isheated overnight at 75° C.

The ethanol is removed in vacuo, and the aqueous residue is thoroughlyextracted with ether. The combined ether extracts are washed withsaturated aqueous sodium chloride, dried, and concentrated in vacuo togive 70.40 g of tan crystals of 5,8-dihydro-1,4-dimethoxynaphthalene,melting point 48°-50° C.

D. 6,7-Epoxy-5,6,7,8tetrahydro-1,4-dimethoxynaphthalene

To a well-stirred solution of 70.40 g of5,8-dihydro-1,4-dimethoxynaphthalene in 1.5 liters of methylene chlorideat 0°-5° C is added 81.5 g of 85% m-chloroperbenzoic acid over 5minutes, and the resulting mixture is stirred overnight at roomtemperature. The mixture is poured into excess 10% aqueous sodiumhydroxide (0°-5° C) and the layers are separated. The aqueous layer iswashed with methylene chloride and the combined organic layers arewashed with 10% aqueous sodium hydroxide, saturated aqueous sodiumchloride, dried, and concentrated in vacuo to give a tan solid.Trituration with isopropyl ether gives 45 g of tan crystals, meltingpoint 127°-130° C. Recrystallization from isopropyl ether gives needlesof 6,7-epoxy-5,6,7,8-tetrahydro-1,4-dimethoxynaphthalene, melting point130°-131.5° C.

E.trans-1,2,3,4-Tetrahydro-3-[(1-methylethyl)amino]5,8-dimethoxy-2-naphthalenol

A mixture of 10.3 g of6,7-epoxy-5,6,7,8-tetrahydro-1,4-dimethoxynaphthalene in 50 ml ofisopropylamine containing 2.93 ml of absolute ethanol is heatedovernight in a small Parr bomb at 105° C ± 5° C (internal pressure =75-100 psi). The cooled reaction mixture is concentrated in vacuo to11.51 g of tan solid. Trituration with ether gives 10.1 g of material,melting point 141-144° C. Two recrystallizations from ethyl acetate give7.0 g oftrans-1,2,3,4-tetrahydro-3-[(1-methylethyl)amino]-5,8-dimethoxy-2-dimethoxy-2-naphthalenol,melting point 144°-145° C.

Anal. Calc'd for C₁₅ H₂₃ O₃ N: C, 67.89; H, 8.74; N, 5.23.

Found: C, 67.65; H, 8.98; N, 5.14.

EXAMPLE 4 trans-5,6,7,8-Tetrahydro-7(and6)-[(1-methylethyl)-amino[-1,6(and 7)-naphthalenediol

A mixture of 15.3 g of 6,7-epoxy-5,6,7,8-tetrahydro-1-naphthol acetate(prepared as described in Example 1), 4.4 ml of absolute ethanol, and 75ml of isopropylamine is heated overnight in a small Parr bomb at 125° C± 5° C (internal pressure = 75-100 psi). The cooled reaction mixture isconcentrated in vacuo to a viscous oil. This is dissolved in ether andthoroughly extracted with 5% hydrochloric acid. The pH of the combinedacid extracts is adjusted to 7-8 with aqueous sodium hydroxide, and thisis thoroughly extracted with ethyl acetate. The combined extracts aredried and concentrated in vacuo to give 16.66 g of viscous oil (containsN-isopropylacetamide). Trituration of this oil with chloroform yields10.9 g of crudetrans-5,6,7,8-tetrahydro-6-[(1-methylethyl)amino]-1,7-naphthalenediol,melting point 132°-136° C. Two recrystallizations oftrans-5,6,7,8-tetrahydro-7-[(1-methylethyl)amino]-1,6-naphthalenediolfrom ethyl acetate yields the analytical sample (5.25 g) melting point152°-154° C.

Two recrystallizations of crudetrans-5,6,7,8-tetrahydro-6-[(1-methylethylamino)amino]-1,7-naphthalenediol(2.57 g) from ethyl acetate yields the analytical sample (1.07 g),melting point 138°-140° C.

EXAMPLE 5 trans-7(and6)-[(1,1-Dimethylethyl)amino]-5,6,7,8-tetrahydro-1,6(and7)-naphthalenediol

A mixture of 15.3 g of 6,7-epoxy-5,6,7,8-tetrahydro1-naphthol acetate(prepared as described in Example 1), 4.4 ml of absolute ethanol, and 75ml of t-butylamine is heated at 130° C ± 5° C in a small Parr bomb for24 hours. The cooled reaction mixture is concentrated in vacuo to a darkviscous oil, which is taken up in ether and thoroughly extracted with 5%hydrochloric acid. The pH of the combined extracts is adjusted to7.0-7.5 with aqueous sodium hydroxide, and this is thoroughly extractedwith ethyl acetate. The combined extracts are dried and concentrated invacuo to yield 12.81 g of viscous oil (contains N-t-butylacetamide). Thecrude oil is dissolved in benzene and applied to a column of basicalumina (400 g, Activity III). Elution with benzene andbenzene/chloroform mixtures gives non-polar material, includingcrystalline N-t-butyl acetamide. Elution with chloroform yields 3.87 gof crudetrans-7-[(1,1-dimethylethyl)amino]-5,6,7,8-tetrahydro-1,6-naphthalenediol,melting point 123°-127° C, after trituration with ether. Elution with 5%methanol/chloroform yields 2.56 g of crudetrans-6-[(1,1-dimethylethyl)amino]-5,6,7,8-tetrahydro-1,7-naphthalenediol,melting point 97°-102° C, after trituration with ether.

Two recrystallizations of crudetrans-7-[(1,1-dimethylethyl)amino]-5,6,7,8-tetrahydro-1,6naphthalenediolfrom ethyl acetate gives the analytical sample, melting point126.5°-128° C.

Anal. Calc'd for C₁₄ H₂₁ NO₂ : C, 71.45; H, 9.00; N, 5.95

Found: C, 71.67; H, 9.21; N, 5.90.

Two recrystallizations of crudetrans-6-[(1,1-dimethylethyl)amino]-5,6,7,8-tetrahydro-1,7-naphthalenediolfrom benzene gives the analytical sample, melting point 152°-154° C.

Anal. Calc'd for C₁₄ H₂₁ NO₂ : C, 71.45; H, 9.00; N, 5.95.

Found: C, 71.71; H, 9.25; N, 5.77.

EXAMPLE 6trans-1,2,3,4-Tetrahydro-5-methoxy-3-[(1-methylethyl)amino]-2naphthalenol

A solution of 25 mmoles of diazomethane (prepared from 6.0 g ofN-methyl-N'-nitro-N-nitrosoguanidine) in ether at 0°-5° C is added to asolution of 4.42 g oftrans-5,6,7,8-tetrahydro-7-[(1methylethyl)amino]-1,6-naphthalenediol(see Example 4) in 25 ml of methanol, and the resulting solution is leftat 0°-5° C for 48 hours. The excess diazomethane is decomposed by theaddition of a few drops of dilute aqueous acetic acid, and the resultingsolution is concentrated in vacuo. The residue is partitioned between 5%aqueous sodium hydroxide and ethyl acetate, and the layers areseparated. The ethyl acetate solution is washed with 5% aqueous sodiumhydroxide, saturated aqueous sodium chloride, dried, and concentrated invacuo to give a solid. Trituration of this with isopropyl ether gives3.14 g of crude product, melting point 107°-110° C. Tworecrystallizations from ethyl acetate give the analyical sample (1.9 g),melting point 110°-112° C.

Anal. Calc'd for C₁₄ H₂₁ NO₂ : C, 71.45; H, 9.00; N, 5.95. Found: C,71.35; H, 9.30; N, 5.99.

EXAMPLE 7 trans-1,2,3,4-Tetrahydro-3[(1-methylethyl)amino]-2,6(or7)-naphthalenediol A. 1,2,3,4-Tetrahydro-2,3-epoxy-6-naphthol acetate

A solution of 15.12 g of 1,4-dihydro-6-naphthol acetate in 160 ml ofdichloromethane is cooled to 0° C while 10.5 g of m-chlorobenzoic acidis added over 10 minutes. The mixture is stirred overnight at roomtemperature and then poured into a slurry of 100 g of ice and 50 ml of10% aqueous sodium hydroxide. The layers are separated, the aqueouslayer re-extracted with dichloromethane (two 100 ml portions), and thecombined extracts are washed with water, dried, and evaporated in vacuoto give 16 g of the title compound as a yellow liquid.

B. trans-1,2,3,4-Tetrahydro-3-[(1-methylethyl)amino]-2,6(or7)-naphthalenediol

A mixture of 15.3 g of 1,2,3,4-tetrahydro-2,3-epoxy-6-naphthol acetate,4.4 ml of absolute ethanol and 75 ml of isopropylamine is heatedovernight in a small Paar bomb at 130° C ± 10° C. The cooled reactionmixture is concentrated in vacuo. Trituration of this material withether gives 11.25 g of a mixture of isomers having a melting point of116°-150° C. The mother liquor from trituration yields an additional 0.9g of this mixture. The mother liquor from the second trituration isconcentrated in vacuo and applied to a column of basic alumina (ActivityIII). Elution with 5% methylene/chloroform gives 1.47 g of crude isomerB, melting point 125°-130° C after trituration with ether.

Three recrystallizations of the above 11.25 g mixture from ethyl acetategives pure isomer A, melting point 153.5°.155° C.

Two recrystallizations of the 1.47 g sample of crude isomer B from ethylacetate gives pure product, melting point 134.5°-135.5° C.

EXAMPLE 8cis-1,2,3,4-Tetrahydro-3-[(1-methylethyl)amino]-2-naphthalenol,hydrochloride (1:1) A. trans-3-Amino-1,2,3,4-tetrahydro-2-naphthalenol,hydrochloride (1:1)

A solution of 9.29 g of sodium azide in 20 ml of water is added dropwiseto a solution (40° C) of 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol(prepared as described in Example 11) in 200 ml of dioxane, and theresulting solution is refluxed overnight. The cooled reaction mixture isfiltered and concentrated in vacuo, and the residue is taken up inchloroform, washed with water, saturated salt solution, dried, andconcentrated in vacuo to 18.21 g of purple liquid.

The crude azide is dissolved in 250 ml of absolute ethanol andhydrogenated in the presence of 1.0 g of prereduced platinum oxide (Parrshaker-24 hours). During the course of the hydrogenation, the Parrbottle is vented and refilled ten times. The catalyst is filtered off,and the filtrate is concentrated in vacuo to a dark oil which partiallycrystallizes on standing. The crude amino-alcohol is dissolved inisopropanol/methanol and treated with hydrogen chloride saturatedisopropanol, to afford 7.0 g of crystalline hydrochloride. Tworecrystallizations of 1.5 g of this material from isopropanol/methanolgives the analytical sample of the title compound, melting point264°-266° C, dec.

B. trans-3-Benzamido-1,2,3,4-tetrahydro-2-naphthalenol

To a well stirred solution of 3.62 g oftrans-3-amino-1,2,3,4-tetrahydro-2-naphthalenol, hydrochloride (1:1) in30 ml of water at 0-5° C is added 2.1 ml of benzoyl chloride in 10 ml ofbenzene. To this stirred two-phase mixture is added, over 30 minutes at0°-5° C, a solution of 1.45 g of sodium hydroxide in 30 ml ofwater--precipitation of a pink solid begins immediately. After stirringthe mixture for an additional 2 hours at 0°-5° C, the solid is filtered,washed with ether, and dried in vacuo to give 4.2 g of crudetrans-3-benzamido-1,2,3,4-tetrahydro-2-naphthalenol.

C. cis-3-Amino-1,2,3,4-tetrahydro-2-naphthalenol, hydrochloride (1:1)

To 10 ml of thionyl chloride is added, in portions over a 30 minuteperiod, 3.48 g of trans-3-benzamido-1,2,3,4-tetrahydro-2-naphthalenol.The mixture is then heated at 50° C for 2.5 hours. The thionyl chlorideis removed in vacuo, the residue taken up in 40 ml of 10% hydrochloricacid, and the solution is refluxed overnight. The reaction mixture iscooled, the precipitated benzoic acid is filtered off, and the filtrateis concentrated in vacuo to give 2.6 g of crystalline hydrochloride.Recrystallization from isopropanol/methanol gives the analytical sampleof the title compound, melting point 269°-271° C.

Anal. Calc'd for C₁₀ H₁₃ ON·HCl: C, 60.16; H, 7.07; N, 7.01; Cl, 17.76.Found: C, 60.28; H, 6.87; N, 6.99; Cl, 17.67.

D. cis-1,2,3,4-Tetrahydro-3-[(1-methylethyl)amino]-2-naphthalenol,hydrochloride (1:1)

A solution of 1.08 g of amino-alcohol (from the above hydrochloride) and2.2 ml of acetone in 100 ml of absolute ethanol is hydrogenated in thepresence of 1.0 g of pre-reduced platinum oxide. After uptake of oneequivalent of hydrogen, the catalyst is filtered off, and the filtrateis concentrated in vacuo. The solid residue is taken up inisopropanol/ether, chilled, and treated with excess hydrogen chloridesaturated isopropanol to afford 1.00 g of crude product. Tworecrystallizations from isopropanol/methanol give the analytical sampleof cis-1,2,3,4-tetrahydro-3-[(1-methylethyl)amino]-2-naphthalenol,hydrochloride (1:1), melting point 232°-234° C, dec.

Anal. Calc'd for C₁₃ H₁₉ NO·HCl: C, 64.57; H, 8.34; N, 5.79; Cl, 14.68.Found: C, 64.54; H, 8.16; N, 5.76; Cl, 14.91.

EXAMPLE 9trans-1,2,3,4-Tetrahydro-3-[(1-methylethyl)amino]-2-naphthalenol A.6,7-Epoxy-5,6,7,8-tetrahydronaphthalene

A solution of 1,4-dihydronpahthalene (32.5 g) in 300 ml of chloroform iscooled in an ice bath and, while stirring, is treated portionwise with61 g of 85% m-chloroperbenzoic acid. The mixture is stirred overnight atroom temperature. After cooling in an ice bath, the solids are removedby filtration. The filtrate is washed twice with 5% potassium carbonatesolution, dried over magnesium sulfate, filtered and the solvent isremoved in vacuo leaving 37.7 g of yellow partially crystallinematerial. This is distilled from a small amount of solid potassiumcarbonate. After some low boiling material is removed, 16.0 g of6,7-epoxy-5,6,7,8-tetrahydronaphthalene is collected, boiling point95°-110° C at 0.1 mm.

B. trans-1,2,3,4-Tetrahydro-3-[(1-methylethyl)amino]-2-naphthalenol

A solution of 8 g of 6,7-epoxy-5,6,7,8-tetrahydronaphthalene in 50 mleach of isopropylamine and ethanol is heated in a Parr bomb at 130° Cfor two days. The solution is cooled and evaporated in vacuo. Theresidue is triturated with hexane to give 4.8 g of an off-white solid.2.4 g of the solid is dissolved in ethyl acetatemethanol (75:25) andcrystallized to give 0.40 of white solid. The filtrate is thenconcentrated on the steam bath to about 15 ml, and diluted with an equalvolume of hexane. It crystallizes to give 1.37 g oftrans-1,2,3,4-tetrahydro-3-[(1-methylethyl)amino]-2-naphthalenol,melting point, 73°-76° C.

Anal. Calc'd for C₁₃ H₁₉ NO: C, 76.05; H, 9.33; N, 6.82. Found: C,75.85; H, 9.55; N, 6.73.

The hypotensive activity of the compounds of formula I is tested usingthe following method.

Male, spontaneously hypertensive Wistar rats (250 to 300 gms) areprepared surgically according to the method of Weeks and Jones Biol.Med. 104: 646 (1960). Coiled PE 10 tubing is joined by heating to alength of PE 20 tubing. After making an abdominal incision in ananesthetized rat, the PE 10 tubing is inserted, via a needle puncture, ashort distance into the abdominal aorta terminating below the origin ofthe renal arteries. The PE 20 portion of the cannula is passedsubcutaneously to exit at the back of the neck. The cannula is filledwith saline and plugged with a 21 g needle stylet wire.

After a minimum of two days, the rat is placed in a harness similar toModel 1602, Lehigh Valley Electronics. The harness is secured to one endof a tightly-wound steel spring. The other end of the spring is passedthrough the top of the cage containing the rat and is attached to thelower end of a feed-through swivel (Sage, Model 120). The steel springserves as a protective cover for the PE 100 tubing within it thatconnects the rat's arterial cannula to the swivel connector. The upperportion of the swivel is provided with two connections, one to a Stathamtransducer through a rotary fluid switch (Scanivalve, Inc.), the otherto a pressurized saline reservoir that provides a slow flow of salineinto the arterial cannula to minimize the packing of cells at its tip.

The blood pressures of 10 rats can be measured at one time using therotary fluid switch and a single transducer. The switch is programmed toadvance through 12 steps, each of 12 seconds duration. Within each cyclethe following pressures are recorded: (1) atmospheric pressure, (2) 200mm Hg static pressure, (3) rate #1, etc. to (12) rat #10. At the end ofeach cycle the switch returns to position #1, the cycles are repeated at5 minute intervals throughout the experimental period.

The signal from the transducer is recorded on magnetic tape(Hewlett-Packard, Model 3960A Portable Instrumentation Recorder) forsubsequent analysis.

A d.c. voltage signal is introduced through a manually operated toggleswitch to a second track on the magnetic tape to indicate the time whenthe rats are given a drug. Drug dosage is carried out at the end of a30-minute control period and during the approximately 21/2 minuteinterval between completion of one cycle of the rotary fluid switch andcommencement of the subsequent cycle. In this way artifacts resultingfrom handling the animals during drug administration are not introducedonto the tape recording. A timing signal from a crystal oscillator isrecorded on a third track of the tape to permit compensation by thecomputer for variations in tape speed during playback of the data intothe recorder.

Following the experiment, the recorded data is introduced into a PDP-11digital computer through an A/D converter. At this time the followingdata are fed into the computer: date of experiment, rat number and sex,drug code number, dose and route of administration, pH of the solutionused and the computer run number. The computer is programmed to senseand store the peak, nadir and integral of each pulse, as well as thenumber of pulses during 10 seconds of each scan on each rat. Theseparameters are averaged and stored as the systolic, diastolic and meanblood pressure and the heart rate for that time.

Changes in mean blood pressure are rated as follows:

    ______________________________________                                                           Rating                                                     ______________________________________                                         0 to 10% - equivocal                                                                              0                                                        11 to 20% - slight   1                                                        21 to 30% - moderate 2                                                          >30% - marked      3                                                        ______________________________________                                    

The following table shows the changes in mean blood pressure (allchanges were decreases) for spontaneously hypertensive rats treated withthe compound indicated. The change in mean blood pressure is rated usingthe 0-3 scale described above.

                  TABLE                                                           ______________________________________                                                                  Change in                                                                     Mean Blood                                          Compound                  Pressure                                            ______________________________________                                        cis-1,2,3,4-tetrahydro-3-[(1-methylethyl)-                                    amino]-2-naphthaleneol, hydrochloride                                                                   2                                                   trans-1,2,3,4-tetrahydro-3-[(1-methylethyl)-                                  amino]-2,6-naphthalenediol                                                                              3                                                   trans-1,2,3,4-tetrahydro-3-[(1-methylethyl)-                                  amino]-2,7-naphthalenediol                                                                              3                                                   trans-7-[(1,1-dimethylethyl)amino]-5,6,7,8-                                   tetrahydro-1,6-naphthalenediol                                                                          1                                                   trans-6-[(1,1-dimethylethyl)amino]-5,6,7,8-                                   tetrahydro-1,7-naphthalenediol                                                                          1                                                   trans-1,2,3,4-tetrahydro-5-methoxy-3-[(1-                                     methylethyl)amino]-2-naphthalenol                                                                       3                                                   trans-1,2,3,4-tetrahydro-3-[(1-methylethyl)-                                  amino]5,8-dimethoxy-2-naphthalenol                                                                      2*                                                  trans-6-dimethylamino-5,6,7,8-tetrahydro-                                     1,7-naphthalenediol       3                                                   trans-1,2,3,4-tetrahydro-3-[(1-methyl-                                        ethyl)amino]-2-naphthalenol                                                                             3                                                   6,7-trans-5,6,7,8-tetrahydro-7-(iso-                                          propylamino)-1,6-naphthalenediol, hydrochloride                                                         3                                                   6,7-trans-5,6,7,8-tetrahydro-6-(iso-                                          propylamino)-1,7-naphthalenediol, hydrochloride                                                         3                                                   trans-5,6,7,8-tetrahydro-7-[(1-methylethyl)-                                  amino]-1,6-naphthalenediol                                                                              1                                                   trans-5,6,7,8-tetrahydro-6-[(1-methylethyl)-                                  amino]-1,7-naphthalenediol                                                                              3                                                   trans-7-(dimethylamino)-5,6,7,8-tetrahydro-                                   1,6-naphthalenediol       3                                                   trans-5,6,7,8-tetrahydro-7-(methylamino)-                                     1,6-naphthalenediol, acetate salt                                                                       3                                                   ______________________________________                                         *Showed no effect in a separate run.                                     

What is claimed is:
 1. A method of lowering the blood pressure of amammalian host in need thereof which comprises orally administering tosaid mammalian host an effective dose of a compound having the structure##STR8## or a pharmaceutically acceptable salt thereof, wherein R₁ ishydrogen or alkyl; R₂ is alkyl; and R₃ and R₄ are each hydrogen,hydroxyl, alkoxy, or arylalkoxy, at least one of R₃ and R₄ being otherthan hydroxyl; wherein the terms alkyl and alkoxy refer to groups having1 to 8 carbon atoms and wherein the term arylalkoxy refers to an alkoxygroup substituted with phenyl or mono- or di-substituted phenyl whereinthe substituents are halogen, alkyl or alkoxy.
 2. A method in accordancewith claim 1 wherein the compound has the structure ##STR9##
 3. A methodin accordance with claim 2 wherein the compound has the structure##STR10##
 4. A method in accordance with claim 2 wherein the compoundhas the structure ##STR11##
 5. A method in accordance with claim 1wherein R₁ is hydrogen and R₂ is alkyl.
 6. A method in accordance withclaim 1 wherein R₃ and R₄ are each alkoxy.
 7. A method in accordancewith claim 1 wherein the compound administered is6,7-trans-5,6,7,8-tetrahydro-7-(isopropylamino)-1,6-naphthalenediol,hydrochloride.
 8. A method in accordance with claim 1 wherein thecompound administered is6,7-trans-5,6,7,8-tetrahydro-6-(isopropylamino)-1,7-naphthalenediol,hydrochloride.
 9. A method in accordance with claim 1 wherein thecompound administered istrans-7-(dimethylamino)-5,6,7,8-tetrahydro-1,6-naphthalenediol.
 10. Amethod in accordance with claim 1 wherein the compound administered istrans-6-(dimethylamino)-5,6,7,8-tetrahydro-1,7-naphthalenediol.
 11. Amethod in accordance with claim 1 wherein the compound administered istrans-1,2,3,4-tetrahydro-3-[(1-methylethyl)amino]-5,8-dimethoxy-2-naphthalenol.12. A method in accordance with claim 1 wherein the compoundadministered istrans-5,6,7,8-tetrahydro-7-[(1-methylethyl)amino]-1,6-naphthalenediol.13. A method in accordance with claim 1 wherein the compoundadministered istrans-5,6,7,8-tetrahydro-6-[(1-methylethyl)amino]-1,7-naphthalenediol.14. A method in accordance with claim 1 wherein the compoundadministered istrans-7-[(1,1-dimethylethyl)amino]-5,6,7,8-tetrahydro-1,6-naphthalenediol.15. A method in accordance with claim 1 wherein the compoundadministered istrans-6-[(1,1-dimethylethyl)amino]-5,6,7,8-tetrahydro-1,7-naphthalenediol.16. A method in accordance with claim 1 wherein the compoundadministered istrans-1,2,3,4-tetrahydro-5-methoxy-3-[(1-methylethyl)amino]-2-naphthalenol.17. A method in accordance with claim 1 wherein the compoundadministered istrans-1,2,3,4-tetrahydro-3-[(1-methylethyl)amino]-2,6-naphthalenediol.18. A method in accordance with claim 1 wherein the compoundadministered istrans-1,2,3,4-tetrahydro-3-[(1-methylethyl)amino]-2,7-naphthalenediol.19. A method in accordance with claim 1 wherein the compoundadministered iscis-1,2,3,4-tetrahydro-3-[(1-methylethyl)amino]-2-naphthalenol,hydrochloride.
 20. A method in accordance with claim 1 wherein thecompound administered istrans-1,2,3,4-tetrahdyro-3-[(1-methylethyl)amino]-2-naphthalenol.